Tumor metastases to distant organs cause the majority of mortality in breast cancer. There is currently no effective treatment for metastatic breast cancer. We hypothesize that metastatic breast cancer can be effectively treated through targeting the DNA damage response pathways with tissue-specific enrichment of therapeutics. Thus, targeted therapy is achieved through tumor tissue-targeted delivery of targeted therapeutics. We have recently developed a polycation-functionalized nanoporous silicon (PCPS) technology platform for siRNA delivery. This platform has a high loading capacity and protects siRNA from degradation by plasma and tissues enzymes. In addition, it maintains sustained release of therapeutic siRNA nanoparticles that are formed in situ during nanoporous silicon degradation for effective tumor cell uptake. We have also shown that the tumor vascular endothelial cells express a high level of E-selectin, and that an E-selectin thioaptamer (ESTA) binds to the tumor vasculature with high affinity and specificity. In this application, we will functionalize the surface of the PCPS particles with the tumor vasculature-targeting moiety to achieve tumor-specific delivery of siRNA. The system will be applied to treat metastatic breast cancer with focus on triple negative breast cancer (TNBC). TNBC is a sub-group of breast cancer with the lowest treatment success rate. Chemo/radiation therapy induces genome damage that evokes DNA damage response whose primary regulator is the ATM kinase. Down-regulation of ATM kinase enhances cancer cell sensitivity. We will develop an effective treatment through blocking DNA damage response by focusing these Specific Aims: Aim 1. To develop a tumor vasculature-targeted high capacity carrier for siRNA and to study transport of therapeutic siRNA to tumor cells Aim 2. To test synergy between suppression of ATM expression and chemotherapy on killing of human TNBC cells Aim 3. To evaluate therapeutic efficacy from tumor vasculature-targeted ATM siRNA in murine xenograft model of human TNBC bone metastasis and PDX model of breast cancer lung metastasis These studies will demonstrate the effectiveness of tumor tissue-enriched ATM siRNA on sensitizing chemotherapy, and will pave the way for the development of the novel siRNA therapeutics for metastatic breast cancer.